Cooc.hi

ABSTRACT

IN WHICH R1 IS A HYDROGEN OR HALOGEN ATOM OR A TRIFLUOROMETHYL, LOWER ALKOXY, NITRO OR AMINO GROUP R2 IS A FURYL, A THIENYL, CYCLOHEXYL, LOWER ALKYL OR A PHENYL GROUP WHICH MAY BE SUBSTITUTED BY A HALOGEN ATOM OR BY A TRIFLUOROMETHYL, NITRO, LOWER ALKOXY OR LOWER ALKYL GROUP, AND R3 IS A HYDROGEN ATOM OR A LOWER ALKYL GROUP, AND R4 IS A LOWER CARBALKOXY, CARBAMOYL, A NLOWERALKYLCARBAMOYL, A N,N-DILOWERALKYLCARBAMOYL, A N(DILOWERALKYLAMINOALKYL) CARBAMOYL, A GROUP HAVING THE FORMULA -COOC AT IN WHICH CAT IS A CATION OF AN ALKALI METAL OR A SEMICATION OF AN ALKALINE EARTH METAL.   DIAZEPINE   1-R3,2-(O=),3-R4,5-R2,7-R1-2,3-DIHYDRO-1H-1,4-BENZO-   1. A BENZODIAZEPINE HAVING THE FORMULA

Jan. 21, 1975 scHMn'T Re. 248,315

1,4-BBRZODIAZEPINE-2-ONES HAVING A CARBOXYLIC ACID ESTER OR AMIDE GROUPIN THE 3-POSITION Original Filed June 14. 1965 Invenor STOMP SchfmzUnited States Patent O 1,4-BENZODIAZEPINE Z-ONES HAVING A CAR- BOXYLICACID ESTER 0R AMIDE GROUP [N THE 3-POSlTlON Josef Schmitt, deceased,late of Val. de-Mame. LHayles-Roses, France, by Marcelle AmandeGeorgette Schmitt, nee Lecocq, administratrix, Val-deMarne, Ll-lay-lesRoses, France, assignor to Etablissements Clin-Byla, Paris, Franceriginal No. 3,516,988, dated June 23, 1970, Ser. No.

706,713, Feb. 19, 1968, which is a continuation of abandoned applicationSer. No. 463,613. June 14. 1965. Application for reissue Mar. 8, 1972,Ser. No. 232,985 Claims priority, application France, June 15, 1964,

978,360; Apr. 12. 1965, 12,886 Int. CI. C07d 53/06 U.S. Cl. 260-239.3 D21 Claims Matter enclosed in heavy brackets I] appears in the originalpatent but forms no part of this reissue specilication; matter printedin Italics indicates the addition.

made by reissue.

ABSTRACT 0F THE DISCLOSURE Novel benzodiazepne having the formula inwhich R, is a hydrogen or halogen atom or a triuoromethyl, lower alkyl,lower alkoxy, nitro or amino groupI R2 is a furyl, a thienyl,cyclohexyl, a lower alkyl group or a phenyl group which may besubstituted by a halogen atom or by a triuoromethyl, nitro, lower alkoxyor lower alkyl group, and R3 is a hydrogen atom or a lower alkyl group,and R, is a lower carbalkoxy, carbamoyl, an N- loweralkylcarbamoyl, anN,Ndiloweralkylcarbamoyl, an N-(diloweralkylaminoalkyl)carbamoyl, agroup having the formula -COOCat in which Cat is a cation of an alkalimetal or a semication of an alkaline earth metal are prepared bytreating an ortho-aminoarylketimine having the formula NF4-C10 in whichR1, R3, R3, and R, are as defined above and R, is a lower alkyl groupor, when R, is a carbamoyl or -COOCat group, a cation of an alkali metalor semication of an alkaline earth metal, but excluding the case inwhich R, is -COOCat and R5 is -Cat, with an anhydrous lower aliphaticacid or with an anhydrous mineral acid, or, when R. is -COOCat and R5 is-CAT, with a dilute aqueous solution of an acid salt, in particularpotassium dihydrogen orthophosphate, in substantially equimolarproportion or with a weak acid.

This application is a continuation of Ser. No. 463,613, tiled June 14,1965, now abandoned.

This invention relates to pharmacologically useful materials which areortho-aminoarylketimines and, in their cyclic form, benzodiazepines. Theinvention consits in certain new compounds as well as in the processesfor the production thereof.

The ortho-aminoaryl ketimines have, in one tautomeric form, the generalformula -lll ICC

in which R is a hydrogen atom or a group having th general formula R1 isa hydrogen or halogen atom or a triuoromethy lower alkyl, lower alkoxy,nitro or amino group, R, is furyi, a thienyl, a lower cycloalkyl, alower alkyl grou or a phenyl group which may be substituted by a halt:gen atom or by a trilluoromethyl, nitro, lower alkoxy o lower alkylgroup and R, is a hydrogen atom or a lowe alkyl group, R4 is a hydrogenatom. a lower carbalkoxi a carbamoyl, N-loweralkylcarbamoyl, anN,N-dilowei alkylcarbamoyl, an N(diloweralkylaminoalkyl) carbarr oyl,lower alkyl or substituted lower alkyl group, a grou having the generalformula -COOCat in which Cat is cation of an alkali metal or semicationof an alkalin earth metal or a group which, in a naturally occurrina-aminocarboxylic acid, is linked to the carbon ator carrying thea-amino group, and R5 is a lower alkyl grou or, when R, is a carbamoylor COOCat group. a catio of an alkali metal or semication of an alkalineenrt metal, When R, is a halogen atom it is preferably a chit rine atom.When R2 is a lower cycloalkyl group it preferably a cyclohexyl group.

The substituted benzodiazepines, in accordance with th invention, have,[in one tautomeric form] the gener.' formula l Cunt Rt \C RPN tt inwhich R1, R, and R, are as defined above and R, is lower carbalkoxy, acarbamoyl, an N-loweralkylcarbarr oyl, an N,N-diloweralkylcarbamoyl, anN(diloweralky aminoalkyl) carbamoyl, a group having the general fol mula-COOCat in which Cat is a cation of an alka metal or a semication of analkaline earth metal or group which, in a naturally occurringa-aminocarboxyli acid, is linked to the carbon atom carrying the a-amingroup.

In the present specification the alkyl groups, includn those present inalkoxy and aralkyl groups have 1 to carbon atoms in a straight orbranched chain; for exarr ple, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tet tiary butyl, amyl and hexyl groups.

These products corresponding to Formula I may b prepared by a reactionfor which the starting materia is an ortho-amino aryl ketiminerepresented by the ger eral Formula III in which the groups R1, R, andR, are as above define( These ortho-aminoaryl ketimines may be obtaineaccording to the present invention by reacting an orthtaminobenzonitrile having the substituent R, with an er cess of magnesiumalkyl halide or magnesium aryl halitl RzMgX, in which R, is as abovedefined and X is a halc gen atom, particularly bromine. A substantialexcess c the Grignard reagent RgMgX is used, preferably abot 3 to 4molecules per molecule of ortho-aminobenzonitril used. The process maybe carried out in anhydrous cth) ether and the starting materialsallowed to react in boiling solvent for up to about hours. Aftercooling, the magnesium complex is decomposed with an aqueous ammoniumchloride solution and the solvent evaporated. The ortho-amino arylketimine crystallises in most cases spontaneously and may be puried byrecrystallisation from a suitable solvent, in particular from ahydrocarbon such as hexane or cyclohexane.

The ortho-aminoaryl ketimines are thus obtained in the form of paleyellow, well defined crystalline compounds. The yield is generally high,frequently of the order of 80 to 90%. The infrared spectra of thesecompounds agree with the structure indicated and is. moreover, confirmedby elementary analysis. The compounds have, among others, two bandscharacteristic of the vibrational frequency of the N-H bond: a tine linein the region of 3480 crn.-1 (absent if the aromatic amine is secondary)and a wide band at 3270-3300 crn.-1 due to the N-I-I of the imine and tothe chelated NH of the NH2 (or Nl-I-R) group; moreover. the infraredspectra show two bands of vibration in the region of 1600 ctn.-1(1610-1580 cmrl) due to the aromatic C=C conjugated to C=N.

Table l sets out certain imines having the general Formula lll which arenew and which may be prepare. as indicated in the examples givenhereinafter.

The substituted imines having the general Formula I (with the exceptionof the salts of the carboxylic derivatives) may be prepared fromortho-amino aryl ketimines (III and an ester of an a-aminoacetic acid inwhich R, is as above defined other than -COOCat. In the simplest case,this aminoacetic acid ester may be an ester of glycine but it may alsobe an ester of a naturally occurring optically active or racemic a-aminoacid such as alanine, leucine or methionine; lastly. the ester may be aderivative of aminomalonic acid, in particular dimethyl or diethylaminomalonate.

These esters may be used in the form of bases but preferably in the formof salts which are easier to deal with than the base, especially thehydrochloride. The reaction is accompanied by liberation of ammonia,either free or combined in the form of a salt according to the equationgiven below (in which Alk denotes a lower alkyl group):

The reaction may be carried out in a solvent which is inert with respectto the imine III, in particular a lower aliphatic alcohol or ahydrocarbon such as benzene or toluene, and at a temperature betweenroom temperature lti and the reflux temperature of the diluent. Thereaction time may vary between l and 12 hours; the higher thetemperature employed, the shorter will be the reaction time. In certaincases, the reaction product separates spontaneously from the alcoholicsolution at room temperature. Nevertheless. it is advantageous toevaporate off the solvent when the reaction is terminated. extract theproduct with an inert solvent and isolate it by crystallisation from asuitable solvent.

The substituted imines I which have an ester function are obtained inthe form of pale yellow products. in most cases crystalline butsometimes in the form of oils. Their structure is determined byelementary analysis` study of their infrared spectra and the results ofsaid hydrolysis.

As could be expected theoretically. the substituted imines (l) can existin two stereoisometric forms one of which. generally obtained in largerquantity, is characterised by an intramolecular N-l-l hydrogen bondbetween a hydrogen on the amino group and the nitrogen of the iminogroup (forming a chelate ring). ln two of the appended examples (seeExamples 6 and 7) these two forms were isolated by fractionalcrystallisation: in the other cases. the product isolated was generallya crystalline product corresponding to the chelate form.

The infrared spectra, determined in methylene chloride. of the chelateforms have a vibration band of the N-H group in the region of 3480 cm.'l(a line line would not be seen in the case of a secondary amine) and awide band at 3150-3300 crn.-l due to the chelate bond N-H of the groupNH2 (or Niel-R); in the region of 1730-17-10 ct'n.l a vibration band ofC=O of the ester radical; in the region of 1610-1620 cm.-1 a band of thearomatic C=C (and C=N1z at 1203-1180 cm.-1 a C-O--C band (ester) shiftedto 1220 crn.-l in the case of malonic esters. The non-chelate formsditer from the above by the existence of a doublet formed by two finelines due to the N-H vibrations of NH2 (a single line at 3400 Cm."l inthe case of secondary amines) and by the absence of absorption bandsbetween 3150 and 3300 cmf.

Investigation of the hydrolysis of imines (li by a strong mineral acidparticularly hydrochloric acid leads to different results according tothe presence or absence of an internal hydrogen bond; if there is nochelation. the action of hydrochloric acid leads to the formation of thecorresponding ortho-amino ketone due to severing of the imine bond: inthe case ot' internal chelation. the imino bond is not severed and thecorresponding benzodiazepine is formed, the configuration of which ismoreover favourable to cyclisation.

In Table 1I, a certain number of subtituted imines are shown whichcorrespond to the general Formula I above in which R5 is an alkyl group;these imines are all new.

TABLE II NH-Rt Ri I Rl Rt ORL] No. Ri Example 4292 CB1. Cl

We have found that the action of an anhydrous lower aliphatic acid, inparticular glacial acetic acid, on either of the two stereoisomerieforms of the substituted imines (l) as well as on mixtures of these twoforms leads almost exclusively to the corresponding benzodiazepine.Heating for from several minutes to one hour is desirable; after removalof the acid reagent in vacuo and dilution with a suitable solvent, inparticular diethyl ether or diisopropyl ether, the benzodiazepinederivative is obtained directly in crystalline state.

Thus 7-chloro 5 phenyl-2,3-dihydro 1H-benzo[fll,4 diazepine (namedhereinafter compound A) which has already been described by L. H.Sternbach and E. Reeder (Journal of Organic Chemistry 1961, volume 26,page 4936) may be prepared in two stages, giving an overall yield of80%, from the unsubstituted imine 4356 CB without having to separate thetwo stereoisomeric forms of the intermediate substituted imine 4292 CB',the N- methyl derivative (B) of compound A, which is already known (seeabove reference) is obtained in a practically quantitative yield bysubjecting the substituted imine 4361 CB for several minutes to theaction of acetic acid.

Employing the same technique, the derivatives of cornpound A substitutedon the 3 carbon atoms are obtained. For this purpose, it is sufficientfirst to react, according to the process of the invention, the freeimine 4356 CB with the hydrochloride .if a suitably selected a-aminoacid ester without isolating the intermediate substituted imine andproceed with the acetic acid treatment in question. For example, usingthe hydrochlorides of analine, leucine and methionine as reagents, oneobtains the 3-methyl, 3- isobutyl and S-methylthioethyl derivativesrespectively of 7-chloro-5phenyl-2-oxo2,3dihydro 1Hbenzo[f]l,4-

diazepine (compounds C, D, E). The yields vary but are always muchhigher than those indicated in the chemical literature-fot` the samesubstances (Sternbach, Fryer, Metlesics. Reeder, Sach. Sancy andStempel, Journal of Organic Chemistry 1962, volume 27, page 3788).

This method has been extended to the preparation of new benzodiazepinescarrying a carbalkoxy group on the 3-carbon atom. For this purpose, itis sufficient to treat malonic acid derivatives of products of type (l)such as those indicated in Table Il with an aliphatic acid; thesederivatives, obtained by the action of a free imine of Formula Ill onthe hydrochloride of an alkyl aminomalonate, may or may not be isolated.However, the yield is particularly high when crystalline substitutedimines (I) are reacted in acetic acid.

We have found an advantageous modification for the preparation ofbenzodiazepines (1I) without isolation of the substituted imines (l),which modification is particularly recommended in cases in which thegroup R2 in the general Formula Il denotes a phenyl or substitutedphenyl group, R, is a hydrogen atom and R, is a carbalkoxy group.Although these substances are easily obtained by the process describedabove, starting from ketimines III such as 4356 CB the yields aresomewhat low and the results are diicult to reproduce if the quantity ofreactans used is increased, whilst complete purification of the productsby crystallisation is, in some cases, laborious. According to thismodification, the substituted imine (I) such as 4292 CB is formed by theaction of the hydrochloride of an alkyl amino-malonate on the free imine(III) such as 4356 CB, the reaction being carried out in a hydrocarbonsolvent, preferably benzene or toluene, whilst hydrogen chloride gas ispassed through the reaction medium to control the cyclisation withoutfirst isolating the intermediate compound. The resulting benzodiazepinederivative such as 4279 CB is then isolated in the form of thehydrochloride which can subsequently be decomposed into practically purebenzodiazepine.

This improvement is suitable for the preparation of otherbenzodiazepines having the general Formula Il, in particular thosementioned in Table III which may or may not be substituted on the carbonatom in position 3 in the heterocycle. All that is necessary is toreplace the hydrochloride of ethyl aminomalonate by the hydrochlr rideof an alkyl glycine such as ethyl glycine which ma). c may not besubstituted on the methylenic carbon atom.

This procedure is recommended for the synthesis l large quantities ofcompound 4190 CB (Formula ll het R2=cyclohexyl, R3=H, R,=H). The use ofsubstitute or unsubstituted amino-malonic esters or amino-acet esters isnot limited to ethyl ester.

The structure of the new carbalkoxy-3-benzo-diazepine (Il) is obtainednot only from the elementary analysis t these compounds but also from astudy of their infrare spectra and the results of hydrolysis .Theinfrared specti of 3-carbalkoxy benzodiazepine (1I) dissolved in metlylene chloride have the following features. Vibratio bands of the N--Hbond of the lactam group without sul stltuent (if this is the ease):namely a ne line (fre N-H) in the region of 3400 ctn.'1 and a wide band(a tached N-H) in the region of 3200 cm.l. In potassiur bromide, theabsorption due to N-H is often more con plex and may result in thepresence of various bands bi twen 3100 and 3400 cm.1; characteristicbands of th ester group at 1730-1755 C=O) and in the region c 1200 cm.-l(C-O-C); a characteristic band of a secont ary amide at 1660-1700ci'n.-l (absence of the amide l band between 1510 and 1550 cmrl); a bandat 1590 1610 cm.1 (aromatic C=C and C=N-) anke by a less intense band at1560-1580 cm.-I for compound having two phenyl groups conjugated toC=N-.

The treatment of 3carbalkoxy benzodiazepines (ll with a saponifyingagent (for example, an alkali met: hydroxide, preferably aqueous oralcoholic potash) an then with a dilute acid reagent (for example.acetic acid gives rise to hydrolysis and decarboxylation and finalileads to benzodiazepines which are unsubstituted on th 3carbon atom and.for example, to compound A if corr pound 4279 CB is put into thereaction, which completel demonstrates the structure proposed. By thetreatment c the 3-carbalkoxy benzodiazepines (Il) with an alkali suc asaqueous or alcoholic potash, then with an alkylatin agent such asdimethyl sulphate and thereafter with dilute acid such as acetic acid,there are obtained the 1 alkylbenzodiazepines, for example, compound B(diaz: pam) when compound 4279 CB is used. Instead of usin the3-carbalkoxy benzodiazepines (ll) the di-salts obtair able by the actionof an alkali on the compounds (1I may be treated with an alkylatingagent. The action c ammonia or of a primary or secondary amine at roortemperature in a suitable solvent such as methanol cor verts the 3carbalkoxybenzodiazepines (1I) into benzc diazepines carrying an amidefunction, with or withot substituent, in the 3-position.

Nitration of the benzodiazepine derivative 4352 CB i sulphuric acidleads to aromatic derivatives nitrated i the 7-position (cf. 4353 CB);the structure is determine by elementary analysis, by the infraredspectrum (nitr bands at 1530 and 1350 ctn.-l in potassium bromide) an byits hydrolysis accompanied by decarboxylation whic leads to 7nitrophenyl2,3 dihydro-lH-benzo[f]1,4-dia zepine which is already known and hasbeen described b Sternbach, Fryer, Keller, Metlesics, Sach and Steiger iJournal of Medicinal Chemistry 1963, volume 6, page 261 Reduction of thenitro derivative e.g. 4353 CB, for en ample by catalytic means, leads tothe correspondin amono compound carrying a 7-amino group (cf. 435 CB).

The 3-carbalkoxybenzodiazepines (ll) generally hav a higher meltingpoint than the corresponding benzc diazepines which are unsubstituted onthe 3carbon atorrI their solubility in organic solvents is relativelyslight.

Table Ill indicates a certain number of new benzodi azepines (thoseindicated by a number) carrying a sul: stituent in the 3position andobtainable by the process o the invention.

With a view to obtaining products in a convenient watersoluble form forpharmacodynamic studies and clinical use, we have saponied3carbalkoxybenzotli azepines (Il) with an alkali metal hydroxide,preferably potassium hydroxide, in an alcoholic medium. [ln every case,the di-metal salt of the dibasic acid is obtained in accordance with theequation given below:

The infra red spectra of compounds of Table IV[A], determined inpotassium bromide, agree with the structure, in particular the absenceof the C=O bands (amide, acid or ester) between 1650 and 1750 crnrl;moreover, they show among other things a very wide and intenseabsorption band in the region of 3400 cm."l (vibrational fre- Ill)quencies of N-H of highly,l chelatcd NH2) and a wide and complexabsorption in the region of l600-l50 cmf1 (aromatic C=C C=N-, C=O ofcarboxyliite ions).

For ease of manipulation, it is best to viorl; in 95% ethyl alcohol; thetemperature should be between room temperature and the boiling point.The purest products are obtained by operating at room temperature. Thereaction is accompanied by a transient yellow discoloration. For rapiddiscoloration, it is advisable to use at least three cquitalents ofpotassium hydroxide. The yield ot the dipotassium salt is practicallyquantitative. These dimcxil salts tl\'[-A]l. i number of which are giienin Table IV below` are colourless powders (with the exception of thenitro and amino derivatives which are yellow)l very soluble in water andstrongly alkaline in reaction [reaction] On acidilcation, the aqueoussolutions give rise to the corresponding benzodiazepines unsubstitutedon the 3-carbon atom: thus the compound 4306 CB becomes benzodiazepine Aof Table III.

The same salts (lV[-A]) can be obtained by saponification of imineshaving a double ester function of type l. [according to the reactionindicated below:

y-Ntt-ti,

The infra-red spectra of the dipotassiurn salts thus prepared arepractically identical with those of the corresponding salts prepared byopening of the benzodiazepine ring. Moreover, the aqueous solutions ofthe dipotassium salts (prepared by either one or the other method) whentreated with dilute hydrochloric acid undergo decarboxylation andcyclisation to give the same benzodiazepine derivative; for example,4306 CB obtained by either one or the other of the two methods givesrise as a result of this treatment to the benzodiazepine compound (A) ofTable Ill.

Lastly, in] In the case of compound 4306 CB, pharmacodynamic studiesconrm the identity of the products obtained by the two methods.

9 [As regards Formula lV-A, it should be remarked that the analyticalresults obtained, which will be discussed below, are more easilyexplained if one assumes a ring structure such as IV-B or IV-C insteadof the structure IV-A for the compounds considered.

Analytical studies have been carried out especially on compound 4306 CB(compound IV in which R,=Cl, R2=C5H5. R3=H).

Even after prolonged drying of this substance at 50 C. under a highvacuum, the products obtained still contain approximately of the solvent(10% aqueous ethyl alcohol) in which the preparation was carried out.

To determine the quantity of ethyl alcohol, the substance underinvestigation is dissolved in water and the solution obtained isdistilled; the distillate is oxidised with nitrochrome reagent and theexcess reagent is titrated with a solution of ferrocyanide in thepresence of diphenylbenzidine.

To determine the quantity of water, the Kart Fischer method cannot beused owing to the strong basicity of the product, and therefore theproduct is suspended in xylene and water is driven off as an azeotropicmixture.

The determinations of ethyl alcohol and water carried out as indicatedabove show that, in addition to the 10% of solvent retained, the productcan liberate by azeotropic distillation one molecule of water, which isnot easily explained if one assumes the structure lV-B or lV-C.

Elementary analysis of the product dried at 50 C., taking into accountthe quantity of solvent of crystallisation present, agrees with thevalues calculated for one of the three Formulae IV-A, IV-B or IV-C,which are identical in their empirical formulae.

Determination of the basic functions of the molecule yields interestingresults especially if, for example, one compares the potentiometricdiagrams obtained for 4306 CB, for the potassium salt of(7-chloro-5-phenyl-2-oxo- 2,3-dihydro lH-benzolf]-1,4-diazepine)3-carboxylic acid (4311 CB) and for 7chloro5phenyl2oxo2,3dihydro1H-benzo[f] 1,4-diazepine (indicated by the reference A above and inExamples 14 and 15).

In an anhydrous medium consisting of a mixture of chloroform (3 vols.)and acetic acid (l vol.), titration with perchloric acid in acetic acidsolution gives the results shown in the accompanying graph:

For compound 4306 CB (continuous line curve) a first jump in potentialwith an equivalent point located at -370 mv. and a second jump inpotential with an equivalent point located at -600 rnv., the totalvolume of titrating agent added to reach the second equivalent pointbeing 1.5 times the volume added in order to reach the hrs point.

For compound 4311 CB (discontinuous cunel. .1 tirs jump in potentialwith an equivalent point located a -360 mv. and a second potential jumpwith an equitalen point located at -590 mv., the volume added in ordertt reach the second equivalent point being twice the volumi added toreach the first point;

For compound (A) (dotted line) a jump in potentia with equivalent pointsituated at -580 mv.

From these experimental data and tht known formulat of compound 4311 CBand compound (A). it is obviou that the second jump in potentialobtained in the titratiot of compound 4306 CB corresponds toneutralisation o the imine function and that the rst corresponds to neutralisaton of the two other functions, namely:

If one adopts the cyclic Formula lVB or lV-C. thi alcoholic (or enolic)and carboxylic functions; or

lf one adopts Formula IV-A, one of the carboxylt acid functions and theamino group. assuming that tht stcond carboxylic function has too low apK value to bt determined owing to its proximity to the rst carboxyli`acid function.

Protometric determination in an anhydrous mediun would thus not appearto be suitable for distinguishin` between the possible structures. lnfact. the result in ai aqueous medium rather tends to favour a ringstructure if this procedure is adopted, it is not possible to cnrrl outthe determination below pH 7 owing to the precipita tion of compound43ll CB and compound (A): onl functions corresponding to high pl( valuescan be deter mined in this way. Compound 4306 CB determined in n'aqueous medium by means of hydrochloric acid has n equivalent point atpH 9.5, which could be attributed tt an alcoholic (or enolic) functionbut less easily to one o the function of the isomer lV-A.

The possibility should not be excluded that under th operatingconditions, the compound 4306 CB used in thes tests will assume one ofthe isometric forms in preferenc to another. Prolonged heating of thisparticular compouni in the solid state at l00 C. seems to favour theformatio of the IV-A isomer. as indicated by the protometric determination in an aqueous medium, in addition to som alteration of theproduct.

Lastly, it is to be noted that the infrared spectra o compounds of typeV-A` lV-B or TV-C and in partici: lar of 4306 CB and 4335 CB arecompatible with th three formulae proposed.

The invention is not in any way limited to a partcula representativeformula among the group of Formula IV-A. IV-B and IV-C.]

Table IV gives by way of example some dipotassiur salts preparedaccording to the process of the inventior TABLE TVL FORMULA TVA, IYB ORTVC] IVD No. Ri R: Rs Exaniplfl 4306 Cl ClH's H 35. 35 and 52.

ClHs CHI 3T and 3S.

ClHs H 39. CoH: H 40. Col-Ts H 4l and 53. CoFs H 42.

The dlsodlum salt and the calcium salt were also prepared. the latt(4372 CB; Example 44) by double decomposition from the dtpotassui salt.

By carrying out a reaction under the conditions iu described, compound4348 CB, which has an amide grou in the 3-position. gives rise to thecorresponding carboxylic derivatives in which the initial amide group ispreserved.

(4349 CB; example 43) We have further found that the dimeral compound[dimetatl salts] such as those given in Table lV, may, under veryaccurate conditions, be converted into benzodiazepine derivatives (V)carrying on the 3-carbon atom a carboxylic acid function salied by theoriginal cation.

[Compound having the general Formula lV-A, IV-B or lV-C] l N li o CH-CRl- \OK iczN Ra (V) To bring about this reaction, it is sufficient totreat an aqueous solution of the product used with a slightly acidreagent at room temperature, [(that is to say an amount of acid which isjust sufficiently strong to liberate one of the two carboxylicfunctions).] preferably potassium dihydrogen phosphate or carbondioxide. The monopotassium salts (V) as a rule crystallise readilyprovided crystallisation is carried out in a suiciently concentratedsolution since they are less soluble in water than the compounds (IV)from which they are derived. They are therefore obtainable in a highyield.

Their formula having been established by elementary analysis. theirstructure is obtained from the study of their infrared spectra and theirchemical properties. The infra-red spectrac (determined in potassiumbromide) agree with the structure (V) and show, among other things andin contradistinction to compounds (IV), a strong band in the region of1690 crn.-1 due to the C=O of the cyclic amide; also to be noted is theabsence of the amide II band between 1510 and 1550 crn.-l which ischaracteristic of non-cyclic secondary amides. Only the nitro group, ifpresent, gives a band in this region. Moreover, the vibration of the NHbond of the lactam group manifests itself by two very wide bands in theregions of 3400 cm.l and 3100 cm.1. Lastly, an intense and complex bandin the region of 1600-1620 cm.l may be attributed to the vibrations ofthe aromatic C=C and of the C=N and of the C=0 of the carboxyl ion.

Aqueous solutions of compounds V generally have a pH in the neutralregion. Products V are less stable in aqueous solution than thecompounds having two carboxyl groups from which they are derived. Theaqueous solutions liberate the corresponding benzodiazepine derivativesunsubstituted on the 3-carbon atom after standing for several hours atroom temperature or rapidly upon boiling or in the presence of aceticacid at or above room temperature.

Several potassium benzodiazepine 3-carboxylates (V) are shown in Table Vto illustrate this aspect of the in- The following examples illustratethe invention; the melting points are designated by M.Pt.K. M.Pt.M orM.Pt.c according to whether they are measured on a Koer block, on aMaquenne block or in a capillary tube. [In these examples. compounds oftype lV have been named according to the formulae of the "open" typeIV-A without thereby intending to emphasise these formulae in favour ofthe cyclic Formulae lV-B and lV-C indicated earlier] EXAMPLE [EAMPLE] l(2-amino-5-chlorophenyl -phenyl-methane-imine (4356 CB) A solution of228.7 g. (1.5 mols) of 2-amino-5-chlorobenzonitrile in 1800 ml. of dryether is added slowly in the course of about 3.5 hours to a solution ofphenyl magnesium bromide prepared from 109 g. (4.5 gram atoms) ofmagnesium turnings and 848 g. (5.4 mols) of bromobenzene in 3600 ml. ofanhydrous ether, and the mixture then heated under reflux for l5 hours.

The complex is decomposed by stirring the reaction mixture into asolution prepared from 500 g. of ammonium chloride in 2000 ml. of waterto which 3 kg. of crushed ice have been added. After extraction andwashing, the ether is evaporated in vacuo at 40 C. The oily residue istaken up in 500 ml. of petroleum ether and left to crystallise bycooling at 20 C. The yellowish crystals formed are dried (309 g); MPLK:74 C.; yield: 92%.

EXAMPLE 2 Using the method described in Example l but replacingB-amino-S-chlorobenzonitrile by an equimolecular quantity of2-methylamino 5 chloroberizonitrile, compound 4357 CB is obtained in ayield of 61%; yellowish crystals; M.Pt.g: 97 C. (hexane).

EXAMPLE 3 (Z-aminophenyl)phenylmethaneimine (4358 CB) Proceeding as inExample 1 but replacing the 2-amino- 5chlorobenzonitrile by anequimolecular quantity of 2- amino-benzonitrile, this compound isobtained in a yield of about 80% of crude product. Yellowish crystalsare obtained; M PLc: 48 C. (isopropyl ether).

EXAMPLE 4 Proceeding as in Example l but replacing the bromobenzene bythe equimolecular quantity of bromocyclohexane. this compound isobtained in a yield of 81%: Yellowish crystals with double meltingpoint; MPLK: C. and then 95 C.

13 EXAMPLE s This product is obtained by the technique employed inExample l but the bromobenzene is replaced by an equivalent quantity oflbromobutane.

A brownish oil is obtained (yield: 94%) which is used without puricationin subsequent reactions. However. the product may be crystallised insmall quantities from cold petroleum ether; M.Pt.c: 2728 C.(decomposition).

EXAMPLE 6 A mixture of 27,6 g. (0.12 mol) of(Z-amino-S-chlorophenyl)phenyl-methaneimine and 20.7 g. (0.15 mol) ofthe hydrochloride of ethyl glycine in 150 rnl. of methanol is stirred atroom temperature for 2.5 hours. A suspension of a pale yellow solid isobtained which consists of the mixture of imine and ammonium chlorideformed in the reaction. The solvent is evaporated under reduced pressureand the residue taken up in methylene chloride. lt is washed with a 10%aqueous solution of sodium carbonate. then with water, dried over sodiumsulphate and the solvent removed by evaporation. A yellow solid remainsbehind which is crystallised from acetone. 32.4 g. of the crystallineproduct is obtained; M.Pt.K: 130-135C.; yield: 85%.

This product is a mixture of the two stereoisomeric forms and may beused as it is for further reactions.

However, each of these forms can be obtained in the pure state byfractional crystallisation from acetone. They have the following meltingpoints: Chelate form: M.Pt.g 148-150 C., non-chelate form: M PLK 142-l44C.: Mixing these two form lowers the melting point.

EXAMPLE 7 This compound is prepared by the method indicated in Example 6the (2-amino-5chlorophenyl)phenylmeth aneimine being replaced by thestoichiometric quantity of (2-methylamino 5 chloro-phenyl)phenylmethanelmlne.

On crystallisation from hexane. a solid is obtained which consists of amixture of the two stereoisomeric forms MPLK: 70-75 C., yield: 82%.

This mixture can be used as it is for subsequent reactions. However eachof the two forms can be isolated in the pure state by fractionalcrystallisation from hexane.

The melting points of these two forms are as follows: Chelate form:M.Pt.g 110 C., non-chelate form M.Pt.g 85 C.

The mixture of the two forms has a considerably lower melting point.

EXAMPLE 8 Diethyl [2-phenyl-2-(2-amino-5-chlorophenyl)1aza vinyl]malonate (4346 CB) A solution of 9.2 g. (0.04 mol) of (2amino[amono]5chloro-phenyl)phenylmetha.neimine in 16 ml. of absolute alcohol is addeddropwise to a boiling solution of 10.6 g. (0.05 mol) of thehydrochloride of ethyl aminomalonate in 30 ml. of absolute alcohol. Whenthis is completed, the mixture is heated under reflux for 30 minutes andthe solvent is then evaporated [evaported] in vacuo.

The residue is taken up in water and in ether the ethereal solution isdecanted, washed with water dried over sodium sulphate and the solventevaporated. The product is recrystallised from diisopropyl ether. Yellowcrystals are obtained (7.8 g.; yield: 50% M.Pt.x: 106 C.).

14 EXAMPLE 9 This compound is prepared by the method indicati in Example[Eaxample] 8. the (Z-:imino-5-chloro-plienyl phenyl-methane-imine beingreplaced by the stoichiomctr quantity of (2-methylamino 5chlorophenyl)-pheny methane-imine. The product is a yellow solid MP1.;88 C. (isopropyl [isophrophyl] ether). Yield: 15%.

EXAMPLE 10 This compound is obtained by the technique describe inExample 6 the (2-amin0- 5 chlorophenyll-pheny methane-imine beingreplaced by an equimoleculnr qua: tity of(Z-amino-phenyl)phen.'lmethnneimine.

The product is obtained in the form of yellowish cry tals; M.Pt.K: 106C. (isopropyl ether): yicldt 58W.

EXAMPLE l1 Using the same method as described in Example 8 by replacingthe (2-amino-5-chloro-phenyli-phenyl-mcthztn imine by the equimolecularquantity of (2aminophenyl phenyl-methane-imine. compound 4351 CB isobtained a yield of 31% Pale Yellow crystals are obtained; Mlt C.(diisopropyl ether).

It is to be noted that in this method of prepnrnlio a small quantity ofthe cyclised product of 3-carbethox S-phenyl 2oxo-2.3-dihydro-lH-benzolfl-lA-dinzepii (4352 CB) can be isolated fromthe mother liquor addition to the main product.

EXAMPLE l2 EXAMPLE 13 This compound is prepared by the method indicatedExample 6, substituting for (Z-amino-S-chlorophenyl phenyl-methane-iminean equivalent quantity of butyl( amino 5 chloro-phenyl)methaneimine,Yellov. crysta are obtained: MPLK: 9697 C. (isopropyl ether); yielt 55%.

EXAMPLE 14 The same procedure is employed as in Example 6 ar then,without isolating compound 4292 CB, it is tutu up in ml. of acetic acidand heated under retlux ft 30 minutes. The acetic acid is evaporateduntil a d residue is obtained, 250 ml. of diisopropyl ether and 2.' m1.of water are added and the mixture then stirred. yellowish solidseparates which is dried and then wash:

with ether. lt is recrystallised from methyl ethyl ketone. Pale yellowcrystals are obtained.

First crop 23.4 g. MPLK: 214-216 C. Second crop 2.3 g. MPLK: 214-216c C.Yield: about 80%` from the unsubstituted imine. The product is identicalwith the product described by Sternbach and Reeder, Journal of OrganicChemistry 1961, volume 26, page 4936).

Acetic acid is added to a solution of 0.409 g. (0.001 mol) of [thedipotassium salt of [2-phenyl(2amino5 chloro-phenyl)-1azavinyl]malonicacid] [4306 CB] in 4 rnl. of distilled water to adjust the solution topH 4. The solution is heated on a water bath for 15 minutes; a solidprecipitates which is separated, washed with water and dried; weight:0.216 g.: M.Pt.K: 214-216c C.: yield 80%. This product is identical withthe product obtained in Example 14.

6 g. of compound 436| CB are heated under reflux for l minutes in 25 ml.oi acetic acid. The acetic acid is removed in vacuo and the residue istaken up in water and a little ether. A yellowish solid separates;M.Pt.K: 130 C.; the yield is substantially quantitative. It isrecrystallised from diisopropyl ether. Yellowish crystals are obtained(4.4 `2.); M.Pt.K: 132 C.: yield 85% in the first batch. The product isidentical \\ith the known product (see reference above in Example 14).

EXAMPLE 17 7-chloro-3-methyl-5-phenyl2-oxo-2.3-dihydro1H-benzo[fl-l.4-diazepine (C) A mixture of 6.9 g. (0.03 mol) of 4356 CB and51 g. (0.033 mol) of the hydrochloride of the ethyl ester of DL-alaninein 40 cc. of absolute alcohol is heated under reflux for one hour. lt isevaporated to dryness and the residue taken up in methylene chloride anda sodium carbonate solution. The organic layer is separated, washed withwater and dried over sodium sulphate. The solvent is evaporated and theresidue taken up in cc. of acetic acid. lt is heated under reflux for 5minutes and the solvent then evaporated under reduced pressure.Diisopropyl ether is added and the product allowed to crystallise: clearyellow crystals are obtained (5.15 g) M.Pt.K: 224 C. Yield: 60% in therst crop. The product is identical with that described in Journal ofOrganic Chemistry 1962, volume 27, page 3788.

The procedure is the same as described in Example 17 except that thehydrochloride of the ethyl ester of DL- alanine is replaced by thehydrochloride of the ethyl ester of DL-leucine in equimolecularquantity. Compound (D) is obtained in a yield of 48%; M.Pt.K: 213 C.(ethyl acetate). The product is identical with the product described inthe chemical literature (reference given above).

This product is obtained utilising the procedure clescribed in Example17, the hydrochloride of ethyl ester of DL-alanine being replaced bythat of the ethyl ester of DL-methionine. (50% in excess of thetheoretical quantity).

Employing the same treatment after crystallisation from ethyl acetate,7chloro-3(3-thiobutyl)5phenyl2 oxo 2:3 dihydro-1H-benzo[f]-1,4-diazepine(MPLK:

16 184 C.) is obtained in a yield of 50%. The product is identical withthe product described in the chemical literature (reference givenabove).

EXAMPLE 20 This compound is obtained by the procedure described inExample 16, compound 4361 CB being replaced by an equimolecular quantityof compound 4346 CB. Shiny, colourless crystals are obtained; MPLK: 244C. (ethyl acetate). Yield: 74% in the first crop.

A mixture of 9.2 g. (0.04 mol) of compound 4356 CB. 10.6 g. (0.05 mol)of the hydrochloride of ethyl aminomalonate and 5 g. (0.05 mol) oftriethylamine in 45 ml. of absolute ethyl alcohol is heated under reuxfor one hour. The solvent is evaporated under reduced pressure and theresidue taken up in water and ether. The ethereal layer is separated.washed with water and dried over sodium sulphate. After evaporation ofthe solvent, the residue is dissolved in 45 ml. of acetic acid andheated under reflux for l5 minutes. The product is evaporated to drynessunder reduced pressure and taken up in ether. A solid separates which isfiltered by suction and recrystallised from ethyl acetate. Brilliant,colourless crystals are obtained (6.4 g.) MPLK: 244 C.; yield: 47%. Theproduct is identical with that obtained in Example EXAMPLE 22 A solutionof 9.2 g. (0.04 mol) of compound 4356 CB in 20 ml. of methanol is addeddropwise, in the course of one hour 30 minutes, to a boiling solution of9.2 g. (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml.of methanol. When this is completed. heating under reflux is continuedfor 30 minutes and the product then concentrated to dryness underreduced pressure. The residue is taken up in water and ether, theethereal layer separated, the product washed with water and dried oversodium sulphate. The solvent is evaporated under reduced pressure. Theresidue. which consists of the methyl ester homologous with the ethylester described in Example 6, could not be obtained in the crystallinestate. It is dissolved in 25 ml. of acetic acid, heated under reux for15 minutes. the product evaporated to dryness and the residual oil takenup in ether. A colourless solid separates which is ltered by suction andrecrystallised from methanol. Colourless crystals are obtained (4.7 g.):M.Pt.K: 226 C. A second crop (1.5 g.) is obtained on concentration ofthe mother liquor; M.Pt.K: 222 C.; total quantity 6.2 g., correspondingto a yield of 47%.

EXAMPLE 23 This product is prepared by the method described in Example22, the methyl aminomalonate and compound 4356 CB being respectivelyreplaced by ethyl aminomalonate and compound 4357 CB in equimolecularquantities. Light yellow crystals are obtained; M.Pt.K: 180 C. (ethylalcohol): yield: 47%.

13.6% solution of amonia in methanol are left together overnight at roomtemperature. The solid rapidly dissolves and after several hours aprecipitate gradually forms which increases in quantity with passage oftime until the whole mass has solidified. The solid is filtered bysuction and washed with methanol. An additional small quantity ot" thesame product is obtained by concentrating the solution to dryness. Thetwo crops are combined and recrystallised from methanol. Colourlesscrystals are obtained (7 g); MPLM: 22S-256 C.; yield: 74%.

EXAMPLE 25 7-chloro-3-methylaminocarbonyl-S-phenyl2oxo2,3-dihydro-lH-benzo[fll,4diazepine (4367 CB) This product is prepared bythe method of Example 24, the solution of ammonia in methanol beingreplaced by the equivalent quantity of a solution of monomethylamine inmethanol. Colourless crystals are obtained (ethyl alcohol); M. PLM: 294C.; yield: 90%.

This compound is obtained as in Example 24, the solution of ammonia inmethanol being replaced by the equivalent quantity of a solution ofdimethyla .tine in methanol. Colourless crystals are obtained: M.Pt.M=297 C.

This compound is obtained by the procedure employed in Example 24, thesolution of ammonia in methanol being replaced by a solution of2-diethylamino-ethylamine (three times the calculated quantity) in timesits volume of methanol. Colourless crystals arc obtained; MllPLK: 220 C.(ethyl acetate); yield: 90%.

EXAMPLE. 28

This compound is obtained by the method employed in Example 16, compound4361 CB being replaced by an equimolecular quantity of compound 4351 CB.Colourless crystals are obtained; M.Pt.x: 226 C. (ethylacetate); yield:70% in the rst crop.

EXAMPLE 29 The procedure described in Example t4 is employed, compound4292 CB being replaced by an equivalent quantity of compound 4364 CB.

Yellowish crystals are obtained; MPLK: 208 C. (ethyl acetate); yield44%. This product is identical with that described in the literature(see reference in Example 17).

EXAMPLE 30 This compound is obtained by the procedure described inExample 22, the hydrochloride of methylaminomalonate and compound 4356CB being replaced by the equiv alent quantities of, respectively, thehydrochloride of ethyl aminomalortate and (Z-amino 5methy1-phenyl)phenylmethane-imine prepared according to Example 12.

Yellowish crystals are obtained; M.Pt.K: 260 C.: yield EXAMPLE 317nitro3-ethoxycarbonyl-S-phenyl2-oxo-2,3-dihydrolH-benzo[f1-1,4-diazepine(4353 CB) 12.3 g. (0.04 mol) of the nely powdered compound 4352 CB areadded slowly, with stirring, to 50 ml. of concentrated sulphurie acid(66 B.) in such a manner that the temperature does not rise above 25 C.4.8 g. (0.o mol) of powdered potassium nitrate is then gradua added tothe resulting solution at a rate such that t temperature remains below25 C. When this is complex the mixture is stirred for 2 hours 30 minutesat rot` temperature. The reaction mixture is then poured on tr mixtureof crushed ice and ether and allotted to stand l 0.5 hour. The solidwhich separates is ltered by suctit washed with water and with ether. ltis recrystallised irc aa large volume of ethyl acetate. Pale yellowcrystals z obtained (7.7 g.); M.Pt.M: 271 C.; yield; 55%.

EXAMPLE 32 A solution of 4.48 g. (0.0l33 mol) of compound 43 CBdissolved in ml. of dimethylformamide and 1 ml. of ethyl alcohol ishydrogenated at ordinary tempe ture and pressure in the presence ofRaney nickel. 'l theoretical absorption of hydrogen requires about 3 hotAfter filtration of the catalyst and evaporation of solvents underreduced pressure, a solid residue is t tained which is recrystallisedfrom a mixture of dimenth formamide and ethyl alcohol. Pale yellowcrystals are t tained (3.9 g.); MPLM: 305 C. (decomposition); yie

EXAMPLE 33 This product is prepared by the procedure described Example17, compound 4356 CB and the hydrochlor of the ethyl ester of DL-alaninebeing respectively placed by equimolecular quantities of compound 4359and the hydrochloride of ethyl glycine. Yellowish crysl are obtained;MPLK: 210 C. (n-propyl alcohol): )le 71% from the imine. In this case.the intermediate pr uct viz. 1-cyclohexyI-1(2'-amino-5'-chlorophenyl)4o5-oxa-2aza1heptene could not be isolated in the crys line state.

EXAMPLE 34 This product is prepared by the procedure descrihet Example22, methyl aminomalonate and compound 4 CB being respectively replacedby the stoichiometric qu tities of ethyl amiiomalonate and compound 4359CB.

Colourless crystals are obtained, M.Pt.K: 208 C. fet acetate); yield:40%. lt should be noted that in this c: the intermediate diethyl[2-cyclohexyl2(2-amino-5-cl rophenyl)lazavinyll-malonale could not beisolated the crystalline state.

EXAMPLE 35 50 g. of caustic potash are dissolved in 1350 ml. 96% ethylalcohol, and 82 g. (0.25 mol) of compoi 4347 CB are then added all atonce at a temperature about 70 C.

The solid dissolves rapidly to form a yellow solut which then losescolour whilst simultaneously an abund colourless precipitate appears.

After cooling, the solid is filtered by suction and was'` with alcoholat 96 C. The product is dried at ordin temperature in a high vacuum. Acolourless solid is tained (quantitative yield), which is completelysolu in water. The aqueous solution is strongly alkaline in reaction;when acidied with acetic acid and heated on a water bath. it yields aprecipitate of 7-chlorO-5-phenyl-2- oxo-2,3-dihydro-1Hbenzo[f]1,4,diazepine (compound A).

Comments:

(l) The preparation may be carried out by replacing compound 4347 CB bythe corresponding ethyl ester (4279 CB). A similar yield of compound4306 CB is obtained.

(2) The corresponding disodium salt can be obtained in the same mannerby replacing potassium hydroxide by sodium hydroxide.

EXAMPLE 36 7 chloro-2.i-dil:ydro-Z-oxo-S-phenyl-IH-I,1i-benzodiazept'rte-.-carboxylic acid.monopotassium salt, monopotassium hydroxide (4306CB) 2 g. of 4346 CB areadded to a solution of 0.84 g. (0.015 mol) of potassium hydroxide in lml. of water and ml. of methanol and the mixture then heated to reflux.The solid dissolves. giving tfse to a red solution whicl' rapidly losesits colour, a precipitate appearing at the same time. After cooling, thesolid is filtered by suction and washed with methanol. A colourlesssolid is obtained (1.25 g.). This compound is found to be identical withthat prepared in Example 35.

EXAMPLE 37 [Dipotassium salt of [l2-phenyl-2-(2-methylamino5chlorophenyll-laLa-vinyl]malonic acid] (4350 CB, rst preparation) Thisproduct is obtained by the method described in Example 35. compound 4347CB being replaced by a stoichiometric quantity of compound 4366 CB` ltis a colourless powder which is very soluble in water. Yield: 71%. Theaqueous solution is strongly alkaline in reaction.

EXAMPLE 38 The compound may be obtained as described in Example 36,compound 4346 CB being replaced by an equimolecular quantity of compound4362 CB. It is a colourless powder completely soluble in water andidentical with the product of Example 37; yield: 50%.

EXAMPLE 39 This substance is prepared by the method described in Example35, compound 4347 CB being replaced by a stoichiometric quantity ofcompound 4352 CB.

Colourless leaflets are obtained which are completely soluble in waterand strongly alkaline in reaction; substantially quantitative yield.

EXAMPLE 40 This substance is prepared by the procedure given in Example35, compound 4347 CB being replaced by an equimolecular quantity ofcompound 4327 CB. It is obtained in the form of a colourless solidcompletely soluble in water. The yield is practically quantitative.

20 EXAMPLE .t1

[Dipotassium salt of [Z-phenyl-Z--amino-S-nitrophenyl)l-aza-\'inyl]malonic acid] (4335 CBI This compoundis obtained by the procedure described in Example 35, compound 4347 CBbeing replaced by an equimolecular quantity of compound 4353 CB. lt is ayellow powder which dissolves completely in water and is stronglyalkaline in reaction; the yield is substantially' quantitative.

EXAMPLE 42 [Dipotassium salt of [2-phenyl2(2.5-diaminophenyl)- l-azavinyllmalonic acid] (4371 CB) This compound is obtained by the methoddescribed in Example 35, compound 4347 CB being replaced by astoichiometric quantity of compound 4354 CB. It is a yellow solidcompletely soluble in water and having a strongly' alkaline reaction.The yield is quantitative.

EXAMPLE 43 This product is obtained by the method described in Example35, compound 4347 CB being replaced by an equivalent quantity ofcompound 4348 CB. Fine yellow crystals completely soluble in water areobtained in quantitative yield:

EXAMPLE 44 A solution of 0.55 g. (0.00375 mol) of calcium chloridedihydrate in 5 ml. of water is added to it solution of l g. (00025 mol)of [the dipotussium salt oflZ-phenyl-Z-tlamino-S-chlordphenyl)-l-aza-vinyllmalonic acid] (4306 CB)in l5 ml. of water.

A solid separates out immediately. After it has been left to stand forl0 minutes. it is ltered by suction. then washed with a small quantityof water and finally dried at ordinary' temperature in a high vacuum. Ayellowish white solid is obtained which is sparingly soluble in water(0.75 g.)', yield: 80%.

EXAMPLE 45 2.1 g. (0.005 mol) of 4306 CB and 0.68 g. (0.005 moll ofmonopotassium phosphate are dissolved at room temperature in 18 ml. ofwater. Solution proceeds rapidly and then colourless platelets slowlyprecipitate. The product is ltered by suction, washed first with chilledwater and then with absolute alcohol. The product is dried at roomtemperature for 12 hours and then in a high vacuum. 1.8 g. of colourlesscrystals completely soluble in water are obtained. The aqueous solutionhas a substantially neutral reaction; yield: This product isdecarboxylated within a few minutes by heating an aqueous solutionthereof, compound A being obtained in the crystalline state.

EXAMPLE 46 Potassium salt of 3-t5phenyl-2-oxo2.3-dihydro-lH-benzo[f]-1,4-diazepine]carboxylic acid (4338 CB) This compound isobtained by the procedure described in Example 45 compound 4306 CB beingreplaced by an equivalent quantity of compound 4337 CB and the volume ofwater used being reduced by one-half. It is a colourless powder whichdissolves in water, giving a sub' stantially neutral reaction: yield:747e.

EXAMPLE 47 Potassium salt of 3-[7-methyl-5-phenyl-2-oxo-2.3-dihydro-1H-benzo[f]1,4-diazepinel-carboxylic acid (4373 CB) The same procedureis employed as in Example 45 but compound 4306 CB is replaced bycompound 4339 CB in stoichiometric quantity and the volume of water usedis reduced by one-half.

It is a colourless solid completely soluble in water; yield; 45%.

EXAMPLE 48 Potassium salt of 3-[7-nitro-5-phenyl-2-oxo-2.3-dihydro-1H-benzo[f]l,4diazepine]-carboxylic acid (4336 CB) This product isprepared by the method of Example 45, compound 4306 CB being replaced bya stoichiometric quantity of compound 4335 CB and the water used isreduced to one-half the volume.

It is a light yellow powder which dissolves in water to give apracticaly neutral solution; yield: 79%.

EXAMPLE 49 the course of 50 minutes. Precipitation of the hydrochlorideof the ketimine (4356 CB) in the form of orangered crystals is observedto begin at the commencement of the introduction of the ketimine.Heating under reux is continued until the suspended precipitate becomesdiscoloured (ammonium chloride), which takes about 2 hours, and a rapidcurrent of gaseous hydrogen chloride is then bubbled through thereaction mixture for 2 hours while the mixture is kept boiling. Thehydrogen chloride of compound 4279 CB precipitates progressively in theform of an orange powder. The crystals (hydrochloride of 4279 CB andammonium chloride) are cooled, ltered by suction and rinsed with benzeneand ether. To liberate the base, the product is treated with a sodiumcarbonate solution in the presence of methylene chloride. The rganiclayer is separated, dried, the solvent evaporated and the residuetreated with ether. A practically pure white product is thus obtained(441.5 g.; yield 63.5%); M.Pt.x=243244 C.

EXAMPLE 50 423.5 g. (2 mols) of the hydrochloride of ethyl aminomalonateand 1250 mi. of benzene are introduced into an [(2 mols) of(2-amino-phenyl) phenylmethane-imine] apparatus identical with that usedin Example 49. The mixture is heated under reflux and a solution of 391g. (2 mols) of (2amino-phenyl) phenyl methane imine (4358 CB) in 1250ml. of dry benzene is added during the course of 50 minutes. From thecommencement of addition of the latter, the hydrochloride of compound4358 CB precipitates in the form of deep red crystals. To facilitate thecondensation reaction, 62.5 ml. of methanol, Le. 2.5% of the totalsolvent used, are added. The reaction mixure is heated under redux for 4hours until decolorisation of the precipitate has occurred. Theprecipitate at the end of the reaction consists solely of ammoniumchloride. Methanol is removed by azeotropic distillation meth-:mol-benzene) and a fast current of gaseous hydrogen lll chloride isthen bubbled through the mixture for tu hours whilst the reactionmixture is kept boiling. The h drochloride of compound 4352 CBprogressively prceip tutes in the form of an orange powder. The reactionmi ture is cooled, the crystals of the hydrochloride of 43:' CB andammonium chloride are ltered by suction` wnshtV with benzene and withether. To liberate the base. tl hydrochloride is treated in the mannerdescribed in E ample 49 for the hydrochloride of the compound 42'. CB.416 g. of practically pure compound 4352 CB are 0 tained in this way.Yield: M.Pt.K=224-2257 C.

EXAMPLE l The procedure according to Example 49 is employe thehydrochloride of ethyl aminomalonate being replact by the stoichiometricquantity of the hydrochloride l ethyl glycinate, compound 4356 CB beingreplaced l the stoichiometric quantity of compound 4356 CB ai benzene byan equal volume of toluene. Compound 41. CB is linally obtained bydecomposition of its orange-rt hydrochloride, giving a yield of 66.5%;M.Pt.x=280 t EXAMPLE 52 Compound 4306 CB (Formula [Formule] IVIC-A, B arC R1=CL R2ZCGH5,

341.5 g. (l mol) of compound 4279 CB are added z rapidly as possible.with stirring, at 18 to 20 C. to solution o 224 g. (4 mols) of potassiumhydroxide in 5 l2 ml. of ethyl alcohol containing by volume of wate Aclear yellow solution forms after about 2 minutes. Sti ring is stopped;crystallisation of compound 4306 C begins after several minutes and isaccompanied by pr gressive decolorisation. The product is filtered bysuctit after 4 hours, washed with absolute alcohol (500 ml and thendried to constant weight at C. under z absolute pressure of 0.1 mm. 422g. of yellowish whi leaets are obtained.

EXAMPLE 53 Compound 4335 CB (Formula [Formule] lVlf-A, B ar C in R1=NO2,R2=C5H5,

The procedure employed is that described in Examp 52 but compound 4279CB is replaced by an equimolec lar quantity of compound 4353 CB. Thereaction fol|o\ the same course and compound 4335 CB is obtained thesame yield as compound 4306 CB.

EXAMPLE 54 7-chloro-5-phenyl-2-oxo-2,3-dihydrol H-benzo[f] l,4-diazepine(A) A suspension of 6.68 g. (0.02 mol) of compound 42 CB in an aqueoussolution of potassium hydroxide (4.5 of potassium hydroxide in 45 ml. ofwater) is heatl with stirring on a water bath until completely dissolveThere is obtained a strongly yellow coloured solutit which clears aftera few minutes. The hot solution treated with 6 m1. of acetic acid whichcauses a pasty pro uct to separate accompanied by evolution of carbon toxide. Decarboxylation is completed by heating to retti for a shorttime. After the reaction is complete the desirt product crystallises; itis centrifuged, washed with wat and dried at 100 C. in vacuo. M.Pt.x=2l2C. The yie is practically quantitative. A pure product can be obtaini bycrystallisation as described in Example 14.

Instead of an aqueous solution of potassium hydroxic' a solution ofpotassium hydroxide in ethyl alcohol, f example a percent by volumealcohol may be usi the hot solution being treated with acetic acid asdescribt above.

23 EXAMPLE s An aqueous solution prepared by dissolving 7 g. ofpotassium hydroxide in ml. of water is added to an aqueous solution of 3g. of compound 4306 CB, then 1.8 g. of dimethyl sulphate is graduallyadded (about 5 minutes) with stirring. care being taken that thetemperature docs' not rise above C. After the addition is ended. thc`mixture is left for 2 hours at room temperature thzn acidified withacetic acid. A pasty product separates which is covered with diisopropylether, and the suspension thus formed is heated to boiling for a fewminutes; evolution of carbon dioxide takes place. The product is cooled.diluted with ether and the aqueous phase is separated. Upon evaporationof the solvent, there is obtained a residue which is crystallised fromdiisopropyl ether. Yield M.Pt.x=l32 C. The product is identical with theproduct obtained according to Example 16.

A certain number of the compounds described in the present applicationhave been studied with regard to their action on the central nervoussystem, as psycholeptics. myorelaxants and tranquillisers. In addition.the acute toxicity has been determined for a number of these compounds.

The study of certain compounds of known pharmacodynamic and clinicalactivity. such as diazepame and chlorodiazeposide. has been undertakenunder the same experimental conditions. with the same tests and withanimais of the same origin as for thc new compounds. lt has thereby beenpossible to make quantitative comparisions of the activity of thediterent compounds for the di'erent test employed In the series of testsbriey described hereinafter. each compound was tested with the use of v:or six scaled doses on batches of l0 or 20 animals for each dose: it wasthereby possible to determine with sucient ethctitudc bythe method ofprobits the SOP? effective dose (FD Sill. that is to say the dose forwhich half the animals are nro tected and react in a predeterminedmanner according to a particular action.

TESTS EMPLOYED The following tests were employed:

(l) Traction test (mice) This consists in observing when the treatedanimals are capable of retrieving a rod grasped by the front paws only.Inability to carry this out was interpreted as a sign of myorelaxantactivity.

(2) Balance test: rotating rod (mice) This test consists in observingwhether the treated animals are capable of maintaining their balance ona horizontal rod kept in rotation.

Numerous neuroleptic compounds or tranquillisers disturb theequilibration reex.

(3) Anti-convulsant activity (anti-pentetrazole) (mice) Pentetrazole.injected intraperitoneally in a dose of 125 mgfkg. produced fatalconvulsions in of the animals. c

Certain compounds exert a protective action preventing convulsions andpermitting survival.

(4) Anti-convulsant activity (electric shock) (mice) The test consistsin determining the intensity of the electric current required to producea fatal shock in a batch of test animals.

Certain preventively administered compounds effectively protect acertain percentage of animals subjected to an electric current of anintensity which is fatal to untreated animals.

llt

lll

(5) Exploration test (mice) This extremely simple test consists inplacing a mouse at the centre of a oor pierced with lioles .trut innoting how many holes the mouse explores iu 5 minutes [his test iscarried out in a room in which complete silence is obsened and whichcontains no person enc-pt the txperimenter who is seated and still. ltappeals to the curiotity of the animals. The doses of thc compoundsemplotctl are. however. \cry small and considerably less than thoserequired to impair movement. This` simple tcst makes it possible toobserve whether the compounds assayed produce a more or less pronouncedlack of imc:- est in the emironment and it gives information which isinteresting from the clinical point of view with regard to the treatmentof anxiety and restlessness.

(6) Spontaneous motor activity in the rat and mouse and provoked motoractivity The effect of drugs ort voluntary movements oi animals can bestudied statistically by methods the details of which will not bediscussed here. The mous-z, which is an extremely lively animal andmoves about a great deal. is particularly suitable for this type ofexperiment.

Moreover, this spontaneous mobility can be exacerbated by preventiveadministration to the animals of certain substances such as bcnzedrine.mescaline and ritaline.

The experimental results obtained by these methods give minableinformation for clinical purposes with regard to the treatment ofambulatory psvchomotor crises.

(7) Antistrychnine activ ity This test demonstrates the acti\ity ofdrugs against a medullary excitant.

(8) Morphine excitation ln the cat, morphine produces a specific slitteoi et'citm tion with hallucinations which can be attenuated orsuppressed by certain psycholeptic drugs.

1n the mottsc. the action of morphine is different but also manifestedby nttirlsetl central evcitution.

(9) Aggressiveness (cat mouse) In general. 'l5 to 80"? of cats areaggressive when confronted with white mice. Psycholeptics andtranquilliscrs may make the cat indifferent and sometimes e\en amiableto the mouse. Similarly. in the case of cats that are furious andaggressive in relation to humans, diminution or suppression of theinstinctive fear and establishment of a climate of confidence areobserved.

(l0) Combativeness It is possible to make a male rat aggresive towardsanother male rat enclosed in the same cage by passing an electriccurrent of more or less high voltage through the oor of the cage.

This test, like the preceding one, can obviously give information ofclinical value for the treatment of aggression diseases,

(l1) Conditioning test The test used consists in educating rats to avoidan electric current passed through the oor of a cage of two compartmentswhen they change compartments. The animal is rst warned by a lamp whichlights up in the compartment through which the current is passing whilethe other is in relative darkness.

This test` which requires more or less daily training at the rate of 5()times for each rat, makes it possible to follow the animals and notetheir progress. The performances realised at the end of a certain time(3 weeks to one month of training) are fairly constant. the percentageof errors made by adequately gifted subjects being less than t0 and veryoften even zero.

One would imagine that disturbances produced in these performances whichcall upon the memory of animals would be of great importance for thechoice of a new medicament. A deconditioning drug of sufi'icientintensity could have the result of partly depriving the patient of theidea of danger and would consequently require special surveillance ofthe sick persons.

(l2) Potcntiation of narcosis Most psycholepitics are hypnotics in largedoses but many of them can in small doses, without themselves producingan hypnosis, either prolong the time of sleep obtained with a truehypnotic (for example a barbiturate) or appreciably lower the dose ofbarbiturate required to obtain sleep.

In the attached table are summarised all the results obtained in thedifferent tests briey recorded above with certain compounds described inthe present application. compared with various reference substances ofknown clinical activity.

From an examination of the figures given in the table i is found that(l) The two para-nitro derivatives 4335 and 4336 are extremely active indifferent tesis, especially' a myorelaxants and an anticonvulsants inthe test for curi osity; on the other hand, they appear to have lesseffec on the faculties of displacement. Lastly, they have marked effectin diminishing aggressiveness (test for com bativeness).

(2) The compound 4306, very similar to 4335 is als( highly active and inmost of the tests it is at least equa and frequently superior todiazepame.

(3) Compound 4311 is also highly active but slightl less so than 4306.Its activity is slightly less when ad ministered parenterally than whenadministered orally What is claimed is:

TABLE VI.-RECAPITULATING THE ACTIVITIES BTAINED WITH DIFFERENT TESTSlThe figures in the table indica*n the 50% eective doses in mgfk. andthe route o1 administration: P0 per os; IP ==intrapertonealL SC=suhcuianp0ii V-intravi-nous Bcnzeilriiie Acute Spontane-Spontaneprovoked toxicity Traction Equilibra- Antl-pente- ElectricExploraons motor ous motor maior (M) DL50 (M) tion (M) trazole (M) shock(M) tion (M) activlty (R) activity (M) activity (It) Diazepame (compound72D POcQBU 1.60 PO. 4.4 P0 1.7 PO 5 PO PO 25 P0 5 PO 100 PL).

B). 800 Nor-diazepame (com- 3.5 PO 8.6 P0 2.9 PO i) P0 '7.8 PO. 50 PO 5DIO 100 1() und A). Ctiiiirdiazepoxide 20(1);0 80 3 PO i3 P0 5 PO l? P020 P0 iuii ili.

` eoPo 20P eoro inoPo S 10 P() ill) Pil. i |o |'li. 25PO. 50 PU.. )50?0lU PU ).10 l0.. I4 P0 1.7 PO- 5 PO )lili ii).

Cawthesame 1.25 PO. 9.6?0 1,7 P0 BPO 625P0 2510 1010 formula as 4306 CBbut obtained by sponiiication oi the noncyclic intermediate (4346 CB).350GB 10 PO. 7.5 PO 2010 4.3 PO 0 44 PO 3.2 PO )l0 PO i0 P0 10 PO.. 5PO; 4.5 1.65 P0. 2.61?

336GB 80)?0 0.28P0. 1.5 P0 0. PO..." P0 610 50PO 5 PO l0 PO.-." l0P l0}"0 10 PO. 4338 5P0 i0P0 10P0. 10P0.. 10P0. 4339 )10 PO. l0P0 l0P0 10P0TABLE VI.RECAPITULATING THE ACTIVITIES OBTAINED WITH DIFFERENTTESTS-Continued [The figures 1n the table indicate the 50% eective dosesin mgJkg. and the route administration: PO-per os; lP-intraperitoneai;SC =subcuiaiwon-` IV intravenous] Benzedririe t d Mescain Ritaiilriiedvovo e rovo e mvo e factor innotor ihotor Anti- Morphine Aggres- CombatDoulile box Narmtiractivity activity activity strychexcita- Morphineaiveneas iveness conditioning pou-nim- (M) (M) (M) nine (M) tion (M)crisis (C) (CIM) (R) (R) tion (ai) 20 P0 50 P0... 2.5 P0.. 25 50-...- 2580-..-. 25 PO.... Without atleet... 2.51'0.

Dizepame (compound Nor-diampame -compoun A Improved per iormances.

orm

but obtained by sponieation o! the noncyclic inter mediate (4346 CB).4350 CB M-mouse. R-nt, C-eat.

1. A henzodiazepine having the formula /x man1-6:0

V CHR; Rt

CRFN

in which R1 is a hydrogen or halogen atom or a trifluoromethyl. loweralkyl. lower alkoxy, nitro or amino group R, is a furyl, a thienyl.cyclohcxyl, lower alkyl or a phenyl group which may be substituted by ahalogen atom or by a triuoromethyl, nitro, lower alkoxy or lower alkylgroup, and R3 is a hydrogen atom or a lower alkyl group, and R* is alower carbalkoxy, carbamoyl, a N- loweralkylcarbamoyl. aN,Ndilowcralkylcarbamoyl, a N- (diloweralkylaminoalkyl) carbamoyl, agroup having the formula -COOC at in which Cat is a cation of an alkalimetal or a semication of an alkaline earth metal.

[2. A process for producing a benzodiazepine having the formula NRz-CLOin which R R3 and R, are as dened in claim 1 and R4 is a hydrogen atom,a lower carbalkoxy, a carhamoyl, a N-loweralkylcarbamoyl, aN,N-diloweralkylcarbamoyl, a N-(diloweralkylaminoalkyl)carbamoyl (analkyl or substituted alkyl group, or a group having the general formula-COOCat in which Cat is the cation of an alkali metal or the semicationof an alkaline earth metal, which comprises treating anortho-aminoarylketimine having the formula NIIR| in which Rx. Rz, and R3are as dened above, R. is a hydrogen atom, a lower carbalkoxy. acarbamoyl, N-loweralkylcarbamoyl, a N,Ndiloweralkylcarbamoyl, a N-(di-Ioweralkylaminoalkyl)carbamoyl, lower alkyl or, a group having theformula COOCat in which Cat is a cation of an alkali metal or semicationor an alkaline earth metal or a group which, in a natural occuringwaminocarboxylic acid, is linked to the carbon atom carrying thea-arnino group, and R is a lower alkyl group or, when R is a carbamoylor -COOC at group, at a cation ot' an alkali metal or semication of analkaline earth metal, but excluding the case in which lh is -COOCat andR5 is -Cat, with an hydrous lower aliphatic acid or with an anhydrousmineral acid, or, when R4 is -COOCat and R5 is -Cat with a diluteaqueous solution of an acid salt in particular potassium dihydrogenorthophosphate in sibstantially equimolar proportion or with a weakacid.

3. A process according to claim 2 in which the mineral acid ishydrochloric acid gas.

4. A process according to claim 2 in which R, is a hydrogen atom or amethyl group and R1 is a chlorine atom or a nitro group.

5. A process according to claim 2 in which R., is a lower carbalkoxygroup and the product is thereafter treated with ammonia, aloweralkylamine, a diloweralkylamine or a diloweralkylamnoalkylamine.

6. A process according to claim 2 in which R4 is a lower carbalkoxygroup and the product is thereafter saponied and then treated with adilute reactive acid to effect decarboxylation.

7. A process according to claim 2 in which R, is a hydrogen atom and Ris a lower carbalkoxy group and the product is treated with an aqueoussolution of an alkali metal hydroxide in order to produce thecorrespending dialkali metal salt and the said dialkyl metal salt isthereafter treated with an alkylating agent and then with dilute acid.

8. A process according to claim 2 in which R1 is a hydrogen atom and R,a lower carbalkoxy, a carhamoyl, a lower N-alkylcarbamoyl, a lowerN,Ndialkylcarbnmoyl or a lower N(dialkylaminoalkyll-carbamoyl group andthe product is then mono-nitrated with a nitrating agent.

9. A process according to claim 8 in which the mononitrobenzodiazepineis reduced with a reagent known to be capable of reducing an aromaticnitro group to a primary amino group.

l0. A process according to claim 2 in which R4 is a lower carbalkoxygroup and the product is saponied with an alkali metal hydroxide.

11. A process for the preparation of saponication products of abenzodiazepine having the formula RlO /Lll

\C H-COOAlk N wherein R1. R, and R3 are as defined in claim 1, and Alkis a lower alkyl group which process comprises treating saidbenzodiazepine with an alkali metal hydroxide in solution in a loweralkanol.

[12. A process according to claim 2 wherein the orthoamino aryl ketimineis the dipotassium salt of [Z-phenyl- 2(2'-amino5chlorophenyl)1azavinyl]malonic acid and the other reactant is potassium dihydrogenorthophosphate] [13. A process according to claim 2 wherein theorthoamino aryl ketimine is the dipotassium salt of [2phenyl2-(2amino5'nitro phenyl)lazavinyl] malonic acid and the other reactantis potassium dihydrogen orthophosphate.)

16. A process for producing a benzodizepine haring the formula in whichR1, and Rz and R, are as defined in claim I and R is hydrogen. lowercarbalkoxy lower alkyl or i-thiobutyl) which comprises treating attortho-aminoaryl kellmine having the formula NH R:

R| CRpN-CHRPCOORI in which R1, R2. R3. and R are as defined about and R,

is lower alkyl with an anhydrous lower aliphatic acid or with a mineralacid in substantially equimolar proportion. I7. The alkali metalhydroxide or alkaline earth metal hydroxide saponi/icarion product of abenzodiuzepmc having the formula CHR CRFN

wherein R, is a hydrogen or halogen atom or a trifuoromethyl, loweralkyl, lower alkoxy, nitro or amino group,

R, is a furyl, a thienyl, cyclohexyl. lower alkyl or a phenyl groupwhich may be substituted by a halogen atom or by a trifluoromethyl,nitro, lower alkoxy or lower alkyl group, R, is a hydrogen atom or alower alkyl group, and R4 is a lower carbalkory, carbamoyl. a N-loweralkyl carbamoyl. a N,Ndilower alkyl carbamoyl or a N-(diloweralkylaminoalkyl) carbamoyl.

18. The .tapontfication product of claim I7 wherein the saponifyingagent is an alkali metal hydroxide.

J9. The saponification product of7-chloro-3-methoxycarbamoyI-5-phenyl2-oxo2,3dihydrolH-benz0-l,4diazepine and potassium hydroxide.

20. The alkali metal hydroxide saponi'cation product of a3-carbalkoxybenzodiazepine.

2l. The potassium hydroxide saponifcation product of a3-carbalkoxybenzodiazepine.

24. The alkali metal hydroxide or alkaline earth metal hydroxide.tapont'fcation product of a compound having the formula NH-Rl y CooAlkR, "-cnpN-CH cootux wherein R1. R2 and R, are as defined in claim l andAlk is a lower alkyl group.

References Cited 3,410,844 11/1968 McCawlly 260-239-3 HENRY R. JILES,Primary Examiner R. T. BOND, Assistant Examiner U.S. Cl. X.R.

260332.2 A, 397.3, 347.4, 471 A, 518 R, 558 A, 566 R; 424-244, 275, 309,319, 324, 325.

1. A BENZODIAZEPINE HAVING THE FORMULA